Benzimidazoles with antithrombotic activity

ABSTRACT

Novel benzimidazoles having antithrombotic activity. Exemplary are:  
     (a) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,  
     (b) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole, and  
     (c) (R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole.

RELATED APPLICATIONS

[0001] This is a continuation of Ser. No. 09/735,159, filed Dec. 12,2000, now allowed.

FIELD OF THE INVENTION

[0002] The present invention relates to novel benzimidazoles, methodsfor making them, pharmaceutical compositions comprising them, and theiruse as, inter alia, antithrombotic agents.

DESCRIPTION OF THE INVENTION

[0003] The present invention relates to benzimidazoles of generalformula

[0004] the tautomers, the stereoisomers, the mixtures thereof, theprodrugs, the derivatives thereof which contain a group which isnegatively charged under physiological conditions instead of a carboxygroup, and the salts thereof, particularly the physiologicallyacceptable salts thereof with inorganic or organic acids or bases whichhave valuable properties.

[0005] The compounds of the above general formula I wherein R_(a)denotes a straight-chained C₁₋₃-alkyl group which is substituted in the1 position by a pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl groupoptionally substituted by a C₁₋₃-alkyl group and by an amino groupmonosubstituted by a cyano-C₁₋₄-alkyl group, and/or R_(c) denotes acyano group or a 1,2,4-oxadiazol-3-yl group substituted in the 5position by a C₁₋₃-alkyl or phenyl group, while the phenyl substituentmay be substituted by a fluorine, chlorine or bromine atom or by aC₁₋₃-alkyl group, are valuable intermediate products for preparing theother compounds of general formula I, and the compounds of the abovegeneral formula I wherein R_(c) denotes one of the following amidinogroups, and the tautomers, stereoisomers, mixtures thereof, theprodrugs, the derivatives thereof which contain a group which isnegatively charged under physiological conditions instead of a carboxygroup, and the salts thereof, particularly the physiologicallyacceptable salts thereof with inorganic or organic salts, and thestereoisomers thereof, have valuable pharmacological properties,particularly an antithrombotic activity.

[0006] In the above general formula

[0007] R_(a) denotes a straight-chained C₁₋₃-alkyl group wherein thehydrogen atoms may be wholly or partially replaced by fluorine atoms andwhich is substituted in the 1 position

[0008] by a pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl groupoptionally substituted by a C₁₋₃-alkyl group and

[0009] by an amino group which is monosubstituted by acarboxy-C₁₋₄-alkyl, cyano-C₁₋₄alkyl or tetrazolyl-C₁₋₄-alkyl group,

[0010] or by a C₁₋₃-alkyl group which is terminally substituted by anN-(carboxy-C₁₋₃-alkylaminocarbonyl)-amino group optionally substitutedby a C₁₋₃-alkyl group at one or both amino nitrogen atoms, by acarboxy-C₁₋₃-alkoxy, N-(carboxy-C₁₋₃-alkyl)-amino,N-(C₁₋₃alkyl)-N-(carboxy-C₁₋₃alkyl)-amino,N-(carboxy-C₁₋₃alkylsulphonyl)-amino,N-(C₁₋₃alkyl)-N-(carboxy-C₁₋₃alkylsulphonyl)-amino ortetrazolyl-C₁₋₃-alkyl group,

[0011] R_(b) denotes a C₁₋₃-alkyl group and

[0012] R_(c) denotes an amidino group, a cyano group or a1,2,4-oxadiazol-3-yl group substituted in the 5 position by a C₁₋₃-alkylor phenyl group, while the phenyl substituent may be substituted by afluorine, chlorine or bromine atom or by a C₁₋₃-alkyl group.

[0013] The carboxy groups, mentioned in the above definition of thegroups, may also be replaced by a group which can be converted in vivointo a carboxy group or by a group which is negatively charged underphysiological conditions or

[0014] the amino and imino groups mentioned in the above definition ofthe groups may also be substituted by a group which can be cleaved invivo. Such groups are described, for example, in WO 98/46576 and by N.M. Nielson et al. in International Journal of Pharmaceutics 39, 75-85(1987).

[0015] By a group which can be converted in vivo into a carboxy group ismeant for example a hydroxmethyl group, a carboxy group esterified withan alcohol wherein the alcoholic moiety is preferably a C₁₋₆-alkanol, aphenyl-C₁₋₃-alkanol, a C₃₋₉-cycloalkanol, whilst a C₅₋₈-cycloalkanol mayadditionally be substituted by one or two C₁₋₃-alkyl groups, aC₅₋₈-cycloalkanol, wherein a methylene group in the 3 or 4 position isreplaced by an oxygen atom or by an imino group optionally substitutedby a C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkoxycarbonyl orC₂₋₆-alkanoyl group and the cycloalkanol moiety may additionally besubstituted by one or two C₁₋₃-alkyl groups, a C₄₋₇-cycloalkenol, aC₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, a C₃₋₅-alkinol orphenyl-C₃₋₅-alkinol, with the proviso that no bond to the oxygen atomstarts from a carbon atom which carries a double or triple bond, aC₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol having a total of 8 to 10carbon atoms which may additionally be substituted in the bicycloalkylmoiety by one or two C₁₋₃-alkyl groups, a1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula

R_(d)—CO—O—(R_(e)CR_(f))—OH,

[0016] wherein

[0017] R_(d) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl orphenyl-C₁₋₃-alkyl group,

[0018] R_(e) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl orphenyl group and

[0019] R_(f) denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0020] by a group which is negatively charged under physiologicalconditions is meant a group such as a tetrazol-5-yl,phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl,C₁₋₆-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino,trifluoromethylsulphonylamino, C₁₋₆-alkylsulphonylaminocarbonyl,phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl orperfluoro-C₁₋₆-alkylsulphonylaminocarbonyl group

[0021] and by a group which can be cleaved in vivo from an imino oramino group is meant, for example, a hydroxy group, an acyl group suchas a benzoyl group optionally mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms or by C₁₋₃-alkyl or C₁₋₃-alkoxygroups, whilst the substituents may be identical or different, apyridinoyl group or a C₁₋₁₆-alkanoyl group such as the formyl, acetyl,propionyl, butanoyl, pentanoyl or hexanoyl group, a3,3,3-trichloropropionyl or allyloxycarbonyl group, aC₁₋₁₆-alkoxycarbonyl or C₁₋₁₆-alkylcarbonyloxy group wherein hydrogenatoms may be wholly or partially replaced by fluorine or chlorine atoms,such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert. butoxycarbonyl,pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl,decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl,hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy,2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy,isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy,pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy,decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy orhexadecylcarbonyloxy group, a phenyl-C₁₋₆-alkoxycarbonyl group such asthe benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonylgroup, a 3-amino-propionyl group wherein the amino group may be mono- ordisubstituted by C₁₋₆-alkyl or C₃₋₇-cycloalkyl groups and thesubstituents may be identical or different, aC₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl,R_(d)—CO—O—(R_(d)CR_(f))—O—CO, C₁₋₆-alkyl-CO—NH—(R_(g)CR_(h))—O—CO orC₁₋₆alkyl-CO—O—(R_(g)CR_(h))—(R_(g)CR_(h))—O—CO group wherein R_(d) toR_(f) are as hereinbefore defined,

[0022] R_(g) and R_(h), which may be identical or different, denotehydrogen atoms or C₁₋₃-alkyl groups.

[0023] Furthermore, the saturated alkyl and alkoxy moieties whichcontain more than 2 carbon atoms mentioned in the above definitions alsoinclude the branched isomers thereof such as the isopropyl, tert.butyl,isobutyl group, etc., for example.

[0024] Preferred compounds of general formula I mentioned above arethose wherein

[0025] R_(b) and R_(c) are as hereinbefore defined and

[0026] R_(a) is as hereinbefore defined, with the proviso that onesubstituent denotes an unbranched C₁₋₃-alkyl group or a2,5-dihydropyrrolocarbonyl group optionally substituted by a C₁₋₃-alkylgroup,

[0027] or R_(a) denotes an ethyl group which is substituted in the 1position

[0028] by a pyrrolidinocarbonyl group and

[0029] by an amino group, while the amino group is substituted by anethoxycarbonylmethyl group which is substituted in the ethoxy moiety inthe 2 position by a methoxy, dimethylamino or tolyl group, by acarboxymethyl, C₃₋₄-alkoxycarbonylmethyl, cyclohexyloxycarbonylmethyl,3-(C₂₋₃-alkoxycarbonyl)-propyl or tetrazolylmethyl group,

[0030] R_(b) denotes a methyl group and

[0031] R_(c) denotes an amidino group substituted by a benzoyl,methylbenzoyl, fluorobenzoyl group or trifluoromethylbenzoyl group or

[0032] R_(a) denotes an ethyl group which is substituted in the 1position

[0033] by a pyrrolidinocarbonyl group substituted in the 2 position by amethyl group and

[0034] by an amino group, whilst the amino group is substituted by acarboxymethyl or ethoxycarbonylmethyl group,

[0035] R_(b) denotes a methyl group and

[0036] R_(c) denotes an amidino group or

[0037] R_(a) denotes an ethyl group which is substituted in the 1position

[0038] by a pyrrolidinocarbonyl group and

[0039] by an amino group substituted by a carboxymethyl,C₃₋₄-alkoxycarbonylmethyl or tetrazolylmethyl group or

[0040] by a methyl group, whilst the methyl group is substituted by atetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy,ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methyl amino,N-[2-(C₁₋₃-alkoxycarbonyl)-ethyl]-N-methylamino,N-(carboxymethylaminocarbonyl)-N-methyl-amino,N-(C₁₋₃alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino,N-(carboxymethylsulphonyl)-N-methyl-amino orN-(C₁₋₃alkoxycarbonylmethylsulphonyl)-N-methyl-amino group,

[0041] R_(b) denotes a methyl group and

[0042] R_(c) denotes an amidino group,

[0043] the tautomers, the isomers and the salts thereof.

[0044] Particularly preferred compounds of the above general formula Iare the above-mentioned compounds of general formula I with theexception of

[0045] (1)2-[4-(N-phenylcarbonyl-amidino)-phenylaminomethyl]-1-methyl-5-[1-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand

[0046] (2)2-(4-amidinophenylaminomethyl)-1-methyl-5-[-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,

[0047] the tautomers, the isomers and the salts thereof.

[0048] Most particularly preferred compounds of the above generalformula I are those wherein

[0049] R_(a) denotes an ethyl group which is substituted in the 1position by a 2,5-dihydropyrrolocarbonyl group optionally substituted bya methyl group and by an amino group which may be substituted by aC₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl group wherein the C₂₋₄-alkoxy moiety isterminally monosubstituted by a methoxy, dimethylamino, phenyl or tolylgroup, by a carboxy-C₁₋₄-alkyl, cyclohexyloxycarbonyl-C₁₋₄-alkyl ortetrazolyl-C₁₋₄-alkyl group, or by a C₁₋₃-alkyl group which isterminally substituted by an N-(carboxy-C₁₋₃-alkylaminocarbonyl)-aminoor N-(C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylaminocarbonyl)-amino groupoptionally substituted at one or both amino nitrogen atoms by aC₁₋₃-alkyl group, by a carboxy-C₁₋₃-alkoxy,C₁₋₃-alkoxycarbonyl-C₁₋₃-alkoxy,N-(C₁₋₃-alkyl)-N-(carboxy-C₁₋₃alkyl)-amino,N-(C₁₋₃-alkyl)-N-(C₁₋₃alkoxycarbonyl-C₁₋₃alkyl)-amino,N-(C₁₋₃alkyl)-N-(carboxy-C₁₋₃-alkylsulphonyl)-amino orN-(C₁₋₃-alkyl)-N-(C₁₋₃alkoxycarbonyl-C₁₋₃alkylsulphonyl)-amino ortetrazolyl-C₁₋₃alkyl group,

[0050] R_(b) denotes a methyl group and

[0051] R_(c) denotes an amidino group optionally substituted by abenzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group

[0052] or R_(a) denotes an ethyl group which is substituted in the 1position

[0053] by a pyrrolidinocarbonyl group and

[0054] by an amino group, whilst the amino group is substituted by anethoxycarbonylmethyl group which is substituted in the 2 position by amethoxy, dimethylamino or tolyl group, by a carboxymethyl,propyloxycarbonylmethyl, isopropyloxycarbonylmethyl,isobutyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl,3-(C₂₋₃-alkoxycarbonyl)-propyl or tetrazolylmethyl group,

[0055] R_(b) denotes a methyl group and

[0056] R_(c) denotes an amidino group substituted by a benzoyl,methylbenzoyl, fluorobenzoyl group or trifluoromethylbenzoyl group or

[0057] R_(a) denotes an ethyl group which is substituted in the 1position

[0058] by a pyrrolidinocarbonyl group substituted in the 2 position by amethyl group and

[0059] by an amino group, whilst the amino group is substituted by acarboxymethyl or ethoxycarbonylmethyl group,

[0060] R_(b) denotes a methyl group and

[0061] R_(c) denotes an amidino group or

[0062] R_(a) denotes an ethyl group which is substituted in the 1position

[0063] by a pyrrolidinocarbonyl group and

[0064] by an amino group substituted by a carboxymethyl orC₃₋₄-alkoxycarbonylmethyl group or

[0065] by a methyl group, whilst the methyl group is substituted by atetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy,ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methyl-amino,N-[2-(C₁₋₃-alkoxycarbonyl)-ethyl]-N-methyl-amino,N-(carboxymethylaminocarbonyl)-N-methyl-amino,N-(C₁₋₃-alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino,N-(carboxymethylsulphonyl)-N-methyl-amino orN-(C₁₋₃alkoxycarbonylmethylsulphonyl)-N-methyl-amino group,

[0066] R_(b) denotes a methyl group and

[0067] R_(c) denotes an amidino group,

[0068] the tautomers, the isomers and the salts thereof.

[0069] The following may be mentioned as examples of particularlypreferred compounds:

[0070] (1)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,

[0071] (2)2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,

[0072] (3)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,

[0073] (4)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,

[0074] (5)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-[(R,S)-1-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole,

[0075] (6)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazoleand

[0076] (7)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(cyclohexyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]benzimidazole,

[0077] the isomers and the salts thereof.

[0078] According to the invention, the compounds of general formula Iare obtained by methods known per se, for example by the followingmethods:

[0079] a) In order to prepare a compound of general formula I whereinR_(c) denotes a cyano group or a 1,2,4-oxadiazol-3-yl group substitutedin the 5 position by a C₁₋₃-alkyl or phenyl group, while the phenylsubstituent may be substituted by a fluorine, chlorine or bromine atomor by a C₁₃-alkyl group:

[0080] cyclising a compound of general formula

[0081] optionally formed in the reaction mixture

[0082] wherein

[0083] R_(a) and R_(b) are as hereinbefore defined,

[0084] R_(c)′ denotes a cyano group or a 1,2,4-oxadiazol-3-yl groupsubstituted in the 5 position by a C₁₃-alkyl or phenyl group, while thephenyl substituent may be substituted by a fluorine, chlorine or bromineatom or by a C₁₋₃-alkyl group,

[0085] Z₁ and Z₂, which may be identical or different, denote amino,hydroxy or mercapto groups optionally substituted by alkyl groups with 1to 6 carbon atoms or

[0086] Z₁ and Z₂ together denote an oxygen or sulphur atom, an iminogroup optionally substituted by an alkyl group with 1 to 3 carbon atoms,an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms.

[0087] The cyclisation is conveniently carried out in a solvent ormixture of solvents such as ethanol, isopropanol, glacial acetic acid,benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether,diethyleneglycoldimethylether, sulpholane, dimethylformamide ortetraline or in an excess of the acylating agent used to prepare thecompound of general formula II, e.g. in the corresponding nitrile,anhydride, acid halide, ester or amide, for example at temperaturesbetween 0 and 250° C., but preferably at the boiling temperature of thereaction mixture, optionally in the presence of a condensing agent suchas phosphorus oxychloride, thionyl chloride, sulphuryl chloride,sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid,hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid,acetic anhydride, N,N-dicyclohexyl-carbodiimide or optionally also inthe presence of a base such as potassium ethoxide or potassiumtert.butoxide. The cyclisation may, however, also be carried out withouta solvent and/or condensing agent.

[0088] b) In order to prepare a compound of general formula I whereinR_(c) denotes an amidino group:

[0089] reacting a compound of general formula

[0090] optionally formed in the reaction mixture

[0091] wherein

[0092] R_(a) and R_(b) are as hereinbefore defined and

[0093] Z₄ denotes an alkoxy or aralkoxy group such as the methoxy,ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio oraralkylthio group such as the methylthio, ethylthio, n-propylthio orbenzylthio group, with ammonia or with the salts thereof.

[0094] The reaction is conveniently carried out in a solvent such asmethanol, ethanol, n-propanol, tetrahydrofuran or dioxane attemperatures between 0 and 150° C., preferably at temperatures between 0and 80° C., with ammonia or one of its salts such as for exampleammonium carbonate or ammonium acetate.

[0095] A compound of general formula III is obtained for example byreacting a corresponding cyano compound with a corresponding alcoholsuch as methanol, ethanol, n-propanol, isopropanol or benzylalcohol inthe presence of an acid such as hydrochloric acid or by reacting acorresponding amide with a trialkyloxonium salt such astriethyloxonium-tetra-fluoroborate in a solvent such as methylenechloride, tetrahydrofuran or dioxane at temperatures between 0 and 50°C., but preferably at 20° C., or a corresponding nitrile with hydrogensulphide, conveniently in a solvent such as pyridine ordimethylformamide and in the presence of a base such as triethylamineand subsequent alkylation of the thioamide formed with a correspondingalkyl or aralkyl halide.

[0096] c) In order to prepare a compound of general formula I whereinR_(a) contains a carboxy group and R_(c) is as hereinbefore defined:

[0097] Converting a compound of general formula

[0098] wherein

[0099] R_(b) and R_(c) are as hereinbefore defined and

[0100] R_(a)′ has the meanings given hereinbefore for R_(a), with theproviso that R_(a) contains a group which can be converted into acarboxy group by hydrolysis, treatment with an acid or base, thermolysisor hydrogenolysis,

[0101] by hydrolysis, treatment with an acid or base, thermolysis orhydrogenolysis into a compound of general formula I wherein R_(a)contains a carboxy group.

[0102] A group which may be converted into a carboxy group may be, forexample, a carboxyl group protected by a protecting group such as thefunctional derivatives thereof, e.g. the unsubstituted or substitutedamides, esters, thioesters, trimethylsilylesters, orthoesters oriminoesters thereof, which are conveniently converted into a carboxylgroup by hydrolysis,

[0103] the esters thereof with tertiary alcohols, e.g. the tert.butylester, which are conveniently converted into a carboxyl group bytreatment with an acid or thermolysis, and

[0104] the esters thereof with aralkanols, e.g. the benzyl ester, whichare conveniently converted into a carboxyl group by hydrogenolysis.

[0105] The hydrolysis is conveniently carried out either in the presenceof an acid such as hydrochloric acid, sulphuric acid, phosphoric acid,acetic acid, trichloroacetic acid, trifluoroacetic acid or the mixturesthereof or in the presence of a base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide in a suitable solvent such as water,water/methanol, water/ethanol, water/isopropanol, methanol, ethanol,water/tetrahydrofuran or water/dioxane at temperatures between −10 and120° C., e.g. at temperatures between room temperature and the boilingtemperature of the reaction mixture.

[0106] If a compound of formula IV for example contains the tert.butylor tert.butyloxycarbonyl group, this may also be cleaved by treatmentwith an acid such as trifluoroacetic acid, formic acid,p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoricacid or polyphosphoric acid optionally in an inert solvent such asmethylene chloride, chloroform, benzene, toluene, diethylether,tetrahydrofuran or dioxane, preferably at temperatures between −10 and120° C., e.g. at temperatures between 0 and 60° C., or also thermally,optionally in an inert solvent such as methylene chloride, chloroform,benzene, toluene, tetrahydrofuran or dioxane and preferably in thepresence of a catalytic amount of an acid such as p-toluenesulphonicacid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferablyat the boiling temperature of the solvent used, e.g. at temperaturesbetween 40 and 120° C.

[0107] If a compound of formula IV contains the benzyloxy orbenzyloxycarbonyl group, for example, this may also be cleavedhydrogenolytically in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide, preferably at temperatures between 0 and 50° C., e.g.at room temperature, and at a hydrogen pressure of 1 to 5 bar.

[0108] d) In order to prepare a compound of general formula I whereinR_(c) denotes an amidino group which is substituted by a group which canbe cleaved in vivo:

[0109] reacting a compound of general formula

[0110] wherein

[0111] R_(a) and R_(b) are as hereinbefore defined, with a compound ofgeneral formula

Z₅—R₉  (VII),

[0112] wherein

[0113] R₉ denotes the acyl group of one of the abovementioned groupswhich can be cleaved in vivo and

[0114] Z₅ denotes a nucleofugic leaving group such as a halogen atom,e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group.

[0115] The reaction is preferably carried out in a solvent such asmethanol, ethanol, methylene chloride, tetrahydrofuran, toluene,dioxane, dimethylsulphoxide or dimethylformamide optionally in thepresence of an inorganic or a tertiary organic base, preferably attemperatures between 20° C. and the boiling temperature of the solventused.

[0116] With a compound of general formula VII wherein Z₅ denotes anucleofugic leaving group, the reaction is preferably carried out in asolvent such as methylene chloride, acetonitrile, tetrahydrofuran,toluene, acetone/water, dimethylformamide or dimethylsulphoxide,optionally in the presence of a base such as sodium hydride, potassiumcarbonate, potassium tert.butoxide or N-ethyl-diisopropylamine attemperatures between 0 and 60° C.

[0117] e) In order to prepare a compound of general formula I whereinR_(c) denotes one of the abovementioned amidino groups:

[0118] catalytic hydrogenation of a compound of general formula

[0119] wherein

[0120] R_(a) and R_(b) are as hereinbefore defined and

[0121] R_(c)″ denotes a 1,2,4-oxadiazol-3-yl group substituted in the 5position by a C₁₋₃-alkyl or phenyl group, wherein the phenyl substituentmay be substituted by a fluorine, chlorine or bromine atom or by aC₁₋₃-alkyl group, and if necessary subsequent hydrolysis of a compoundthus obtained.

[0122] The catalytic hydrogenation is preferably carried out in asuitable solvent such as methanol, ethanol, ethanol/water, glacialacetic acid, ethanol/glacial acetic acid, ethyl acetate, dioxane ordimethylformamide in the presence of a hydrogenation catalyst such aspalladium/charcoal, preferably at temperatures between 0 and 50° C.,e.g. at room temperature, and at a hydrogen pressure of 1 to 5 bar.

[0123] The hydrolysis which may follow is conveniently carried outeither in the presence of an acid such as hydrochloric acid, sulphuricacid, phosphoric acid, acetic acid, trichloroacetic acid,trifluoroacetic acid or mixtures thereof or in the presence of a basesuch as lithium hydroxide, sodium hydroxide or potassium hydroxide in asuitable solvent such as water, water/methanol, water/ethanol,water/isopropanol, methanol, ethanol, water/tetrahydrofuran orwater/dioxane at temperatures between −10 and 120° C., e.g. attemperatures between room temperature and the boiling temperature of thereaction mixture.

[0124] f) In order to prepare a compound of general formula I whereinR_(a) denotes an amino-C₁₋₃-alkyl group in which the amino group ismonosubstituted by a carboxy-C₁₋₄-alkyl or tetrazolyl-C₁₋₃alkyl group:

[0125] alkylating a compound of general formula

[0126] wherein

[0127] R_(b) and R_(c) are as hereinbefore defined and

[0128] R_(a)″ denotes an amino-C₁₋₃-alkyl group, with a compound ofgeneral formula

R_(a)′″—Z₇  (X)

[0129] wherein

[0130] R_(a)′″ denotes a carboxy-C₁₋₄-alkyl or tetrazolyl-C₁₋₄-alkylgroup and

[0131] Z₇ denotes a nucleofugic leaving group such as a halogen atom ora sulphonic acid ester group, e.g. a chlorine, bromine or iodine atom,or a p-nitrophenyl group.

[0132] The alkylation is conveniently carried out in a solvent such asmethylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide,dimethylformamide or acetone, optionally in the presence of a reactionaccelerator such as sodium or potassium iodide and preferably in thepresence of a base such as sodium carbonate or potassium carbonate or inthe presence of a tertiary organic base such as N-ethyl-diisopropylamineor N-methyl-morpho-line, which may simultaneously also act as solvent,or optionally in the presence of silver carbonate or silver oxide attemperatures between −30 and 100° C., but preferably at temperaturesbetween −10 and 80° C.

[0133] If according to the invention a compound of general formula I isobtained wherein R_(a) contains a carboxy group, this may subsequentlybe converted by esterification into a corresponding compound whereinR_(a) contains an esterified carboxy group, and/or

[0134] if a compound of general formula I is obtained wherein R_(a)contains an esterified carboxy group, this may subsequently be convertedby transesterification into a corresponding compound wherein R_(a)contains another esterified carboxy group, and/or

[0135] if a compound of general formula I is obtained wherein R_(a)contains a cyano group, this may subsequently be converted into acorresponding compound wherein R_(a) contains a tetrazolyl group.

[0136] The subsequent esterification is carried out with a correspondingalcohol, usefully in a solvent or mixture of solvents such as methylenechloride, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane, but preferably in an excess of thealcohol used, optionally in the presence of an acid such as hydrochloricacid or in the presence of a dehydrating agent, e.g. in the presence ofisobutyl chloroformate, thionyl chloride, trimethylchlorosilane,hydrochloric acid, sulphuric acid, methanesulphonic acid,p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexyl carbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N′-carbonyldiimidazole orN,N′-thionyldiimidazole, triphenylphosphine/carbon tetrachloride ortriphenylphosphine/diethyl azodicarboxylate, optionally in the presenceof a base such as potassium carbonate, N-ethyl-diisopropylamine orN,N-dimethylamino-pyridine, conveniently at temperatures between 0 and150° C., preferably at temperatures between 0 and 80° C., or with acorresponding halide in a solvent such as methylene chloride,tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide oracetone, optionally in the presence of a reaction accelerator such assodium or potassium iodide and preferably in the presence of a base suchas sodium carbonate or potassium carbonate or in the presence of atertiary organic base such as N-ethyl-diisopropylamine orN-methyl-morpholine, which may also serve as solvent at the same time,or optionally in the presence of silver carbonate or silver oxide attemperatures between −30 and 100° C., but preferably at temperaturesbetween −10 and 80° C.

[0137] The subsequent transesterification is carried out with acorresponding alcohol, conveniently in a solvent or mixture of solventssuch as methylene chloride, benzene, toluene, chlorobenzene,tetrahydrofuran, benzene/tetrahydrofuran or dioxane, but preferably inan excess of the alcohol used, conveniently in the presence of an acidsuch as hydrochloric acid or in the presence of a compound such as2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane attemperatures between 0 and 150° C., preferably at temperatures between 0and 80° C.

[0138] The subsequent conversion of a cyano group into a tetrazolylgroup is preferably carried out in a solvent such as benzene, toluene ordimethylformamide at temperatures between 80 and 150° C., preferably at120 and 130° C. The hydrazoic acid needed is conveniently liberatedduring the reaction from an alkali metal azide, e.g. from sodium azide,in the presence of a weak acid such as ammonium chloride. The reactionmay also take place with another salt or derivative of hydrazoic acid,preferably with aluminium azide or tributyl tin azide, the tetrazolecompound optionally obtained in this way being liberated from the saltcontained in the reaction mixture by acidification with a dilute acidsuch as 2N hydrochloric acid or 2N sulphuric acid.

[0139] In the reactions described hereinbefore, any reactive groupspresent such as carboxy, amino or alkylamino groups may be protectedduring the reaction by conventional protecting groups which are cleavedagain after the reaction.

[0140] For example, a protecting group for a carboxy group may be atrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup and

[0141] protecting groups for an amino or alkylamino group may be anacetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groupand additionally, for the amino group, a phthalyl group.

[0142] Any protecting group used is optionally subsequently cleaved forexample by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, acetic acid/water, tetrahydrofuran/water ordioxane/water, in the presence of an acid such as trifluoroacetic acid,hydrochloric acid or sulphuric acid or in the presence of an alkalimetal base such as lithium hydroxide, sodium hydroxide or potassiumhydroxide or by ether cleavage, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 100° C., preferablyat temperatures between 10 and 50° C.

[0143] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group iscleaved hydrogenolytically, for example, with hydrogen in the presenceof a catalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 50° C., but preferablyat room temperature, and at a hydrogen pressure of 1 to 7 bar, butpreferably 3 to 5 bar.

[0144] A methoxybenzyl group may also be cleaved in the presence of anoxidant such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesbetween 0 and 50° C., but preferably at room temperature.

[0145] A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisol.

[0146] A tert.butyl or tert.butyloxycarbonyl group is preferably cleavedby treating with an acid such as trifluoroacetic acid or hydrochloricacid, optionally using a solvent such as methylene chloride, dioxane orether.

[0147] A phthalyl group is preferably cleaved in the presence ofhydrazine or a primary amine such as methylamine, ethylamine orn-butylamine in a solvent such as methanol, ethanol, isopropanol,toluene/water or dioxane at temperatures between 20 and 50° C.

[0148] An allyloxycarbonyl group is cleaved by treating with a catalyticamount of tetrakis-(triphenylphosphine)-palladium(O), preferably in asolvent such as tetrahydrofuran and preferably in the presence of anexcess of a base such as morpholine or 1,3-dimedone at temperaturesbetween 0 and 100° C., preferably at room temperature and under inertgas, or by treating with a catalytic amount oftris-(triphenylphosphine)-rhodium(I)chloride in a solvent such asaqueous ethanol and optionally in the presence of a base such as1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70° C. Thecompounds of general formulae II to X used as starting materials, someof which are known from the literature, are obtained by methods knownfrom the literature, and moreover their preparation is described in theExamples.

[0149] The chemistry of the compounds of general formula II is describedfor example by Jack Robinson in J. Chem. Soc. 1941, 744, that of thebenzimidazoles is described by Katritzky and Rees in ComprehensiveHeterocyclic Chemistry, Oxford, Pergamon Press, 1984, by Schaumann inHetarene III, Methoden der organischen Chemie (Houben-Weyl), 4thedition, published by Thieme, Stuttgart 1993.

[0150] Thus, for example, a compound of general formula II is obtainedby acylating a corresponding o-diamino compound with a correspondingreactive acyl derivative,

[0151] a compound of general formulae III, IV, VI, VIII and IX isobtained by cyclising a corresponding, substituted compound according toprocess a) and if necessary subsequently converting a cyano compoundthus obtained into the desired starting compound using known methods.

[0152] Moreover, the compounds of general formula I obtained may beresolved into their enantiomers and/or diastereomers.

[0153] Thus, for example, the compounds of general formula I obtainedwhich occur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes and compounds ofgeneral formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

[0154] The enantiomers are preferably separated by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a(+)-or (−)-menthyloxycarbonyl.

[0155] Furthermore, the compounds of formula I may be converted into thesalts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

[0156] Moreover, if the new compounds of formula I contain a carboxygroup, they may subsequently, if desired, be converted into the saltsthereof with inorganic or organic bases, particularly for pharmaceuticaluse into the physiologically acceptable salts thereof.

[0157] Suitable bases for this purpose include for example sodiumhydroxide, potassium hydroxide, cyclohexylamine, ethanolamine,diethanolamine and triethanolamine.

[0158] As already mentioned, the new compounds of general formula I andthe salts thereof have valuable properties. Thus, the compounds ofgeneral formula I wherein R_(c) denotes a cyano group are valuableintermediate products for preparing the other compounds of generalformula I, and the compounds of general formula I wherein R_(c) denotesone of the amidino groups mentioned hereinbefore, and the tautomers, thestereoisomers and the physiologically acceptable salts thereof havevaluable pharmacological properties, particularly an antithromboticeffect which is preferably based on influencing thrombin or factor Xa,e.g. on an inhibitory effect on thrombin or factor Xa, on an effect ofprolonging the aPTT time and an inhibitory effect on related serineproteases such as e.g. trypsin, urokinase factor VIIa, factor IX, factorXI and factor XII.

[0159] For example, the following compounds:

[0160]A=2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride,

[0161]B=(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochlorideand

[0162] C=(2)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride

[0163] were investigated as follows for their effects on prolonging theaPTT time:

[0164] Materials: plasma, from human citrated blood.

[0165] PTT reagent, Boehringer Mannheim (524298),

[0166] Calcium solution (0.025 mol/l), Behring Werke, Marburg (ORH056/57),

[0167] Diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH60/61),

[0168] Biomatic B 10 coagulometer, Desaga, Wiesloch.

[0169] Method:

[0170] The aPTT time was determined using a Biomatic B 10 coagulometermade by Messrs. Desaga.

[0171] The test substance was placed in the test tubes prescribed by themanufacturer together with 0.1 ml of human citrated plasma and 0.1 ml ofPTT reagent. The mixture was incubated for three minutes at 37° C. Theclotting reaction was started by the addition of 0.1 ml of calciumsolution. The time is measured using the apparatus from the addition ofthe calcium solution up to the clotting of the mixture. Mixtures towhich 0.1 ml of DBA buffer were added were used as the controls.

[0172] According to the definition, a dosage-activity curve was used todetermine the effective concentration of the substance, i.e. theconcentration at which the aPTT time is doubled compared with thecontrol.

[0173] The Table which follows contains the results found: aPTT timeSubstance (ED₂₀₀ in μM) A 0.13 B 0.12 C 0.22

[0174] The compounds prepared according to the invention are welltolerated since no toxic side effects could be detected at therapeuticdoses; moreover, the corresponding prodrugs, for example the compoundsof Examples 1(6), 2, 3(2) and 3(5), exhibit good oral resorption.

[0175] In view of their pharmacological properties the new compounds andthe physiologically acceptable salts thereof are suitable for theprevention and treatment of venous and arterial thrombotic diseases,such as for example the treatment of deep leg vein thrombosis, forpreventing reocclusions after bypass operations or angioplasty (PT(C)A),and occlusion in peripheral arterial diseases such as pulmonaryembolism, disseminated intravascular coagulation, for preventingcoronary thrombosis, stroke and the occlusion of shunts. In addition,the compounds according to the invention are suitable for antithromboticsupport in thrombolytic treatment, such as for example with rt-PA orstreptokinase, for preventing long-term restenosis after PT(C)A, forpreventing metastasis and the growth of clot-dependent tumours andfibrin-dependent inflammatory processes, e.g. in the treatment ofpulmonary fibrosis.

[0176] The dosage required to achieve such an effect is appropriately0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and0.1 to 50 mg/kg, preferably 0.3 to 30 mg/kg by oral route, in each caseadministered 1 to 4 times a day. For this purpose, the compounds offormula I prepared according to the invention may be formulated,optionally together with other active substances, with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethyleneglycol,propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fattysubstances such as hard fat or suitable mixtures thereof, to produceconventional galenic preparations such as plain or coated tablets,capsules, powders, suspensions or suppositories.

[0177] The Examples which follow are intended to illustrate theinvention:

EXAMPLE 1

[0178](R)-2-[4-[N-(4-methyl-phenylcarbonyl)-amidino]-phenylamino-methyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0179] a.(R)-5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidin-2,4-dione

[0180] 10.0 g (4.45 mmol) of(R)-5-(4-chlorophenyl)-5-methyl-imidazolidin-2,4-dione are addedbatchwise to 50 ml of fuming nitric acid at −25 to −35° C. After 45minutes at −25 to −20° C. the reaction mixture is poured onto ice water.The crystalline product is suction filtered, washed with water anddried.

[0181] Yield: 10.5 g (100% of theory),

[0182] Melting point: 173-178° C.

[0183] R_(f) value: 0.30 (silica gel; cyclohexane/ethyl acetate=1:1)

[0184] b. (R)-2-amino-2-(4-chlor-3-nitro-phenyl)-propionic acid

[0185] 10.5 g (0.044 mol) of(R)-5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidine-2,4-dione arerefluxed in 200 ml of dioxane and 700 ml of 6N hydrochloric acid for 5days. The solution is concentrated by evaporation, the residue is takenup in water and extracted with ethyl acetate. The aqueous phase isconcentrated by evaporation, mixed with toluene and evaporated todryness. The residue is triturated with ether, suction filtered anddried.

[0186] Yield: 6.8 g (63% of theory),

[0187] R_(f) value: 0.24 (Reversed phase RP8, 5% salinesolution/methanol=1:1)

[0188] c.(R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionicacid

[0189] 72.5 g (0.296 mol) of(R)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid are dissolved in850 ml dioxane and 200 ml water and after the addition of 108.7 ml (0.78mol) of triethylamine and 136 g (0.623 mol) of di-tert.butyl dicarbonatestirred for 18 hours at room temperature. After the addition of 800 mlof 1N sodium hydroxide solution the solution is stirred for 30 minutesand then extracted 3× with 500 ml of ether. The aqueous phase isadjusted to pH 7 with 1N hydrochloric acid and then to pH 4 with 5%citric acid. After extracting 4 times with 500 ml of ethyl acetate, thecombined organic phases are washed with water, dried, suction filteredthrough magnesium sulphate and concentrated by evaporation.

[0190] Yield: 86.8 g (85% of theory),

[0191] R_(f) value: 0.3 (silica gel; methylene chloride/methanol=4:1+1%ammonia) C₁₄H₁₇ClN₂O₆ (344.7)

[0192] Mass spectrum: (M−H)⁻=343

[0193] d.(R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3-nitro-phenyl)-propionicacid

[0194] 96 g (0.278 mol) of(R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionicacid and 440 ml of methylamine solution (40% solution in water) areheated to 90° C. in a pressurised vessel for seven hours. After cooling,the reaction solution is adjusted to pH 3.5 by the addition of glacialacetic acid, whilst cooling with ice, and extracted with ethyl acetate.After the solvent has been evaporated off, the residue remaining iswashed with ether and dried.

[0195] Yield: 70 g (74% of theory),

[0196] R_(f) value: 0.30 (silica gel; methylene chloride/ethanol=19:1+1%glacial acetic acid)

[0197] C₁₅H₂₁N₃O₆ (339.3)

[0198] Mass spectrum: (M−H)⁻=338

[0199] e.(R)-2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonlamino-1-prrolidino-propanone

[0200] 50 g (0.147 mol) of(R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3-nitro-phenyl)-propionicacid are dissolved in 275 ml of dimethylformamide and after the additionof 47.5 g (0.147 mol) ofO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,24.5 g (0.334 mol) of pyrrolidine and 30 ml of (0.273 mol) ofN-methyl-morpholine the mixture is stirred for 20 hours at roomtemperature. The solution is poured onto ice water and acidified withcitric acid (pH 5-6). The precipitate formed is suction filtered, washedwith water and dried.

[0201] Yield: 45.5 g (79% of theory),

[0202] R_(f) value: 0.6 (silica gel; petroleum ether/ethyl acetate=1:1)

[0203] f.(R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone

[0204] 25.5 g (65 mmol) of(R)-2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanoneare dissolved in 650 ml of methanol and after the addition of 4.0 g ofpalladium on activated charcoal (20%) the mixture is hydrogenated for 2hours at room temperature. Then the catalyst is filtered off andconcentrated by evaporation.

[0205] Yield: 21.4 g (91% of theory),

[0206] R_(f) value: 0.31 (silica gel; ethyl acetate +1% ammonia)

[0207] g.(R)-2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone

[0208] Prepared analogously to Example 1e from(R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate,4-cyano-phenylglycine and N-methyl-morpholine in dimethylformamide.

[0209] Yield: 100% of theory,

[0210] R_(f) value: 0.47 (silica gel; ethyl acetate)

[0211] h.(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0212] 47.7 g (0.042 mol) of(R)-2-[4-methylamino-3-(4-cyanophenylamino-methylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanoneare refluxed in 300 ml of glacial acetic acid for 2 hours. The reactionmixture is added to ice water and adjusted to pH 8 with conc. ammonia.The precipitate formed is filtered off, washed with water and dried.

[0213] Yield: 46 g (100% of theory),

[0214] R_(f) value: 0.3 (silica gel; ethyl acetate +1% ammonia)

[0215] i.(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0216] 25.1 g (50 mmol) of(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare dissolved in 500 ml of 6N hydrochloric acid at 35° C. and stirredfor one hour at this temperature. The solution is mixed with ice, madealkaline with ammonia and extracted with ethyl acetate. The combinedorganic extracts are dried and concentrated by evaporation.

[0217] Yield: 17.8 g (88% of theory),

[0218] R_(f) value: 0.5 (silica gel; methylene chloride/ethanol=4:1+1%ammonia)

[0219] k.(R)-2-(4-cyanophenylaminomethyl)-1-methyl-S-(1-ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0220] 4.2 g (10.44 mmol) of(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare dissolved in 100 ml of acetone and combined with 2.3 g (16.65 mmol)of potassium carbonate and 2.25 ml (20.2 mmol) of ethyl bromoacetate.The suspension is heated to 60° C. for 5 hours. After cooling thereaction mixture is stirred into 400 ml of ice water, the precipitateformed is filtered off, washed with water and dried. The crude productis chromatographed on silica gel, eluting with methylenechloride/ethanol (19:1 and 9:1). The uniform fractions are combined andconcentrated by evaporation.

[0221] Yield: 3.1 g (61% of theory),

[0222] R_(f) value: 0.4 (silica gel; ethyl acetate/ethanol=9:1)

[0223] l.(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1-ethoxycarbonylethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride

[0224] 6.8 g (13.8 mmol) of(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare dissolved in 400 ml of saturated ethanolic hydrochloric acid andstirred for 23 hours at room temperature. The solvent is distilled off,the residue is dissolved in 200 ml of absolute ethanol and combined with20 g (0.21 mol) of ammonium carbonate. After 20 hours at roomtemperature 100 ml of ethanol are added and after another 10 hours'stirring at room temperature the mixture is filtered and evaporated todryness. The residue is stirred in 200 ml of acetone, filtered off,washed with ether and dried.

[0225] Yield: 7.6 g (100% of theory),

[0226] R_(f) value: 0.61 (Reversed phase RP8; 5% sodium chloridesolution/methanol=3:2)

[0227] C₂₇H₃₆N₇O₃×HCl (505.64/542.09)

[0228] Mass spectrum: (M+H)⁺=506

[0229] m.(R)-2-[4-[N-(4-methyl-phenylcarbonyl)-amidino]-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0230] A suspension of 0.7 g (1.2 mmol) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloridein 25 ml of methylene chloride is combined with 4.0 ml (28 mmol) oftriethylamine and 0.8 g (3.0 mmol) of 4-nitrophenyl 4-methyl-benzoateand heated to 50° C. for 3.5 hours, whereupon a clear solution isformed. After cooling, it is washed with sodium bicarbonate solution,saline solution and water, dried over magnesium sulphate andconcentrated by evaporation. The crude product is purified on silicagel, eluting with ethyl acetate/ethanol (50:1 and 9:1). The uniformfractions are combined, concentrated by evaporation, triturated withether, suction filtered and dried.

[0231] Yield: 0.5 g (66% of theory),

[0232] R_(f) value: 0.50 (silica gel; ethyl acetate/ethanol=9:1)

[0233] C₃₅H₄₁N₇O₄ (623.75)

[0234] Mass spectrum: (M+H)⁺=624

[0235] (M+Na)⁺=646

[0236] (M−H)⁻=622

[0237] The following compounds are obtained analogously to Example 1:

[0238] (1)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(isopro-pyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate

[0239] Yield: 69% of theory,

[0240] R_(f) value: 0.2 (silica gel; methylene chloride/ethanol=7:3+1%glacial acetic acid)

[0241] C₂₈H₃₇N₇O₃×CH₃COOH (519.65/579.70)

[0242] Mass spectrum: (M+H)⁺=520

[0243] (M−H)⁻=518

[0244] (2)(R)-2-[4-[N-(4-fluorophenylcarbonyl)amidino]-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0245] Yield: 40% of theory,

[0246] R_(f) value: 0.4 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0247] C₃₄H₃₈FN₇O₄ (627.72)

[0248] Mass spectrum: (M+H)⁺=628

[0249] (M+Na)⁺=650

[0250] (M−H)⁻=626

[0251] (3)(R)-2-[4-[N-(4-trifluoromethyl-phenylcarbonyl)amidino]-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0252] Yield: 47% of theory,

[0253] R_(f) value: 0.53 (silica gel; methylene chloride/methanol/conc.ammonia=9:0.9:0.1)

[0254] C₃₅H₃₈F₃N₇O₄ (677.73)

[0255] Mass spectrum: (M+H)⁺=678

[0256] (M+Na)⁺=700

[0257] (M−H)⁻=676

[0258] (4)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0259] (5)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride

[0260] Yield: 94% of theory,

[0261] R_(f) value: 0.2 (Reversed phase RP8; 5% salinesolution/methanol=2:3)

[0262] C₂₇H₃₃N₇O₃×2 HCl (503.6/576.51)

[0263] Mass spectrum: (M+H)⁺=504

[0264] (M−H+HCl)⁻=538/540 (Cl)

[0265] (6)2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole

[0266] Yield: 71% of theory,

[0267] R_(f) value: 0.3 (silica gel; ethyl acetate/ethanol=9:1)

[0268] C₃₄H₃₇N₇O₄ (607.72)

[0269] Mass spectrum: (M+H)⁺=608

[0270] (M+Na)⁺=630

[0271] (M−H)⁻=606

[0272] (7)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-[(R,S)-1-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochloride(mixture of diastereomers)

[0273] Yield: 88% of theory,

[0274] R_(f) value: 0.3 (Reversed phase RP8; 5% saline solution/methanol30=3:2)

[0275] C₂₈H₃₇N₇O₃×2 HCl (519.65/592.56)

[0276] Mass spectrum: (M+H)⁺=520

[0277] (M+Cl)⁻=554/6 (Cl)

[0278] (8)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(3-ethoxycarbonyl-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0279] Yield: 19% of theory,

[0280] R_(f) value: 0.44 (silica gel; methylene chloride/methanol=4:1+1%glacial acetic acid)

[0281] C₃₆H₄₃N₇O₄ (637.79)

[0282] Mass spectrum: (M+H)⁺=638

[0283] (M−H)⁻=636

[0284] (9)(R)-2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0285] Yield: 70% of theory,

[0286] R_(f) value: 0.37 (silica gel; ethyl acetate/ethanol 9:1)C₃₅H₄₉N₇O₅ (647.82)

[0287] Mass spectrum: (M+Na)⁺=670

[0288] (M−H)⁻=646

EXAMPLE 2

[0289](R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0290] A solution of 0.3 g (0.53 mmol) of(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazolein 5 ml of n-butanol is mixed with 0.1 g (0.46 mmol) of2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane andstirred for 1 hour at room temperature. The reaction mixture is purifiedon silica gel, eluting with ethyl acetate/ethanol/conc. ammonia(50:0.95:0.05 and 20:0.95:0.05). The uniform fractions are combined andconcentrated by evaporation.

[0291] Yield: 0.19 g (57% of theory,

[0292] R_(f) value: 0.45 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0293] C₃₆H₄₃N₇O₄ (637.78)

[0294] Mass spectrum: (M+H)⁺=638

[0295] (M+Na)⁺=660

[0296] (M−H)⁻=636

[0297] The following compounds are obtained analogously to Example 2:

[0298] (1)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0299] Yield: 16% of theory,

[0300] R_(f) value: 0.48 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0301] C₃₆H₄₃N₇O₄ (637.78)

[0302] Mass spectrum: (M+H)⁺=638

[0303] (M+Na)⁺=660

[0304] (M−H)⁻=636

[0305] (2)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-methoxy-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0306] Yield: 43% of theory,

[0307] R_(f) value: 0.31 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0308] C₃₅H₄₁N₇O₅ (639.76)

[0309] Mass spectrum: (M+H)⁺=640

[0310] (M−H)⁻=638

[0311] (3)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-dimethylamino-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0312] Yield: 23% of theory,

[0313] R_(f) value: 0.26 (silica gel; methylenechloride/methanol/ammonia=9:0.9:0.1)

[0314] C₃₆H₄₄N₈O₄ (652.8)

[0315] Mass spectrum: (M+H)⁺=651

[0316] (M−H)⁻=653

[0317] (4)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-(2-methylphenyl)-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0318] Yield: 23% of theory,

[0319] R_(f) value: 0.52 (silica gel; ethylacetate/ethanol/ammonia=9:0.95:0.05)

[0320] C₄₁H₄₅N₇O₄ (699.86)

[0321] Mass spectrum: (M+H)⁺=700

[0322] (M+Na)⁺=722

[0323] (M−H)⁻=698

[0324] (5)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(cyclohexyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0325] Yield: 34% of theory,

[0326] R_(f) value: 0.49 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0327] C₃₈H₄₇N₇O₄ (663.83)

[0328] Mass spectrum: (M+H)+664

[0329] (M+Na)⁺=686

[0330] (M−H)⁻=662

EXAMPLE 3

[0331](R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole

[0332] 2.1 ml of conc. sulphuric acid are added dropwise to a solutionof 0.5 g (0.82 mmol) of(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazolein 12.3 ml of isopropanol. After 4 hours at 85° C. the solution iscooled and poured onto 250 ml of ice water. The pH is adjusted to 8.5 bythe addition of conc. ammonia. The precipitate formed is suctionfiltered, dried and purified on silica gel, eluting with methylenechloride +2% methanol +0.01% ammonia. The uniform fractions are combinedand concentrated by evaporation, the residue is triturated with ether,filtered off and dried.

[0333] Yield: 0.19 g (37% of theory),

[0334] R_(f) value: 0.46 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0335] C₃₅H₃₉N₇O₄ (621.75)

[0336] Mass spectrum: (M+H)⁺=622

[0337] (M+Na)⁺=644

[0338] (M−H)⁻=620

[0339] The following compounds are obtained analogously to Example 3:

[0340] (1)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole

[0341] Yield: 33% of theory,

[0342] R_(f) value: 0.46 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0343] C₃₅H₃₉N₇O₄ (621.75)

[0344] Mass spectrum: (M+H)⁺=622

[0345] (M+Na)⁺=644

[0346] (M−H)⁻=620

[0347] (2)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0348] Yield: 36% of theory,

[0349] R_(f) value: 0.45 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0350] C₃₅H₄₁N₇O₄ (623.76)

[0351] Mass spectrum: (M+H)⁺=624

[0352] (M+Na)⁺=646

[0353] (M−H)⁻=622

[0354] (3)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-butyl-oxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride

[0355] Yield: 8% of theory,

[0356] R_(f) value: 0.44 (silica gel; methylene chloride/methanol=4:1+1%ammonia)

[0357] C₂₉H₃₉N₇O₃×2 HCl (533.69/606.6)

[0358] Mass spectrum: (M+H)⁺=534

[0359] (M−H)⁻=532

[0360] (4)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-pro-pyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-sulphate

[0361] Yield: 7% of theory,

[0362] R_(f) value: 0.36 (silica gel; methylene chloride/methanol=4:1+1%ammonia)

[0363] C₂₈H₃₇N₇O₃×H₂SO₄ (519.65/617.7)

[0364] Mass spectrum: (M+H)⁺=520

[0365] (5)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(cyclohexyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole

[0366] Yield: 22% of theory,

[0367] R_(f) value: 0.60 (silica gel; ethyl acetate/ethanol 9:1+1%ammonia)

[0368] C₃₈H₄₃N₇O₄ (661.81)

[0369] Mass spectrum: (M+H)⁺=662

[0370] (M+Na)⁺=684

[0371] (M−H)⁻=660

[0372] (6)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(3-(isopropyloxycarbonyl)-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0373] (7)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(3-(n-propyloxycarbonyl)-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

EXAMPLE 4

[0374](R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0375] a. 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-ethyl acetate

[0376] Prepared analogously to Example 1k from4-(5-methyl-1,2,4-oxadiazol-3-yl)-aniline and ethyl bromoacetate inN-ethyl-diisopropylamine.

[0377] Yield: 78% of theory,

[0378] R_(f) value: 0.60 (silica gel; ethyl acetate/petroleum ether=1:1)

[0379] b.4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonylamino-ethylacetate

[0380] Prepared analogously to Example 1c from4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-ethyl acetate anddi-tert.butyldicarbonate/N-ethyl-diisopropylamine in dioxane.

[0381] Yield: 63% of theory,

[0382] R_(f) value: 0.48 (silica gel; ethyl acetate/cyclohexane=1:2)

[0383] c.4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminoaceticacid

[0384] A solution of 3.5 g (9.7 mmol) of4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonylamino-ethylacetate in 10 ml of tetrahydrofuran and 4 ml of methanol is combinedwith 9.7 ml of 1N sodium hydroxide solution (9.7 mmol) and stirred for 3hours at room temperature. The reaction mixture is evaporated down tohalf its volume and mixed with water. The pH value is adjusted to 4-5 bythe addition of glacial acetic acid, the precipitate formed is filteredoff, washed with water and dried.

[0385] Yield: 2.8 g (87% of theory),

[0386] R_(f) value: 0.5 (Reversed phase RP8; 5% salinesolution/methanol=1:3)

[0387] d.(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminomethyl]-1-methyl-5-[2-tert.butyloxycarbonylamino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0388] Prepared analogously to Example 1 g/h from(R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone,4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminoaceticacid and carbonyldiimidazole in tetrahydrofuran and subsequently treatedwith glacial acetic acid.

[0389] Yield: 47% of theory,

[0390] R_(f) value: 0.46 (silica gel; ethyl acetate)

[0391] e.(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0392] Prepared analogously to Example 1i from(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminomethyl]-1-methyl-5-[2-tert.butyloxycarbonyl-amino-1-(pyrrolidino-carbonyl)-ethyl]-benzimidazoleand 6N hydrochloric acid.

[0393] Yield: 91% of theory,

[0394] R_(f) value: 0.44 (silica gel; methylenechloride/methanol/ammonia=9:0.9:0.1)

[0395] f.(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-cyanomethylamino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0396] Prepared analogously to Example 1k from(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand bromoacetonitrile/potassium carbonate in acetone.

[0397] Yield: 72% of theory,

[0398] R_(f) value: 0.54 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia)

[0399] C₂₇H₃₀N₈O₂ (498.59)

[0400] Mass spectrum: (M+H)⁺=499

[0401] (M−H)⁻=497

[0402] (M+Na)⁺=521

[0403] g.(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0404] 1.1 g (2.2 mmol) of(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-cyanomethylamino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare suspended in 20 ml of toluene and 60 ml of dioxane and combined with2.2 g (6.6 mmol) of tributyl tin azide. The reaction mixture is heatedto 130° C. for 6 hours. After the solvent has been evaporated off, theresidue is triturated with petroleum ether, filtered, washed withpetroleum ether and dried. The crude product is purified on silica gel,eluting with methylene chloride/methanol 20:1 and 9:1. The uniformfractions are combined and concentrated by evaporation.

[0405] Yield: 0.7 g (59% of theory)

[0406] R_(f) value: 0.33 (silica gel; methylene chloride:methanol=9:1)

[0407] C₂₇H₃₁N₁₁O₂ (541.6)

[0408] Mass spectrum: (M−H)⁻=540

[0409] (M+Na)⁺=564

[0410] h.(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0411] Prepared analogously to Example 1 h from(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand hydrogen/palladium (20% on activated charcoal) in ethanol/glacialacetic acid.

[0412] Yield: 63% of theory,

[0413] R_(f) value: 0.35 (Reversed phase RP8; 5% salinesolution/methanol=4:3)

[0414] C₂₅H₃₁N₁₁O (501.6)

[0415] Mass spectrum: (M+H)⁺=502

[0416] (M−H)⁻=500

EXAMPLE 5

[0417]2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate

[0418] a. methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate

[0419] 35 ml of a 1.6 molar solution of n-butyllithium in hexane (61mmol) are added dropwise to a solution of 8.1 ml of diisopropylamine (85mmol) in 20 ml of tetrahydrofuran at −78° C. Then a solution of 10.0 g(50 mmol) of methyl 2-(4-chloro-phenyl)-propionate in 30 ml oftetrahydrofuran is added dropwise at −78° C. Gaseous formaldehyde ispiped into the reaction mixture at −20° C. for 30 minutes. After theaddition of 5% citric acid and glacial acetic acid the mixture isextracted with ethyl acetate. The organic phases are washed with 1Nsulphuric acid, water, saturated sodium bicarbonate solution and salinesolution and dried over magnesium sulphate. The crude product ispurified on silica gel, eluting with cyclohexane/ethyl acetate (19:1;9:1; 4:1; 1:1 and 0:1). The uniform fractions are combined andconcentrated by evaporation.

[0420] Yield: 9.7 g of yellow oil (84% of theory),

[0421] R_(f) value: 0.25 (silica gel; petroleum ether/ethyl acetate=4:1)

[0422] b. 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid Preparedanalogously to Example 8 from methyl2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate and sodium hydroxidesolution in ethanol.

[0423] Yield: 83% of theory,

[0424] R_(f) value: 0.55 (silica gel; ethyl acetate/cyclohexane=2:1+1%glacial acetic acid)

[0425] c. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-nitroxy-propionic acid

[0426] Prepared analogously to Example 1a from2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid and nitric acid.

[0427] Yield: 90% of theory,

[0428] Melting point: 129-132° C.

[0429] C₁₀H₉ClN₂O₇ (304.64)

[0430] d. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-hydroxy-propionic acid

[0431] Prepared analogously to Example 1i from2-(4-chloro-3-nitro-phenyl)-3-nitroxy-2-methyl-propionic acid and 6Nhydrochloric acid in dioxane.

[0432] Yield: 98% of theory,

[0433] C₁₀H₁₀ClNO₅ (259.65)

[0434] Mass spectrum: (M−H)⁻=258/60 (Cl)

[0435] (2M−H)⁻=517/9 (Cl₂)

[0436] e.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-propionicAcid

[0437] Prepared analogously to Example 1e from2-(4-chloro-3-nitro-phenyl)-3-hydroxy-2-methyl-propionic acid andN-methyl-benzylamine.

[0438] Yield: 81% of theory,

[0439] C₁₈H₂₀ClN₂O₅ (344.37)

[0440] Mass spectrum: M⁺=344

[0441] f.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one

[0442] Prepared analogously to Example 1e from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionicacid and pyrrolidine.

[0443] Yield: 96% of theory,

[0444] C₂₂H₂₇N₃O₄ (397.48)

[0445] Mass spectrum: M⁺=398

[0446] (M+Na)⁺=420

[0447] g.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-ethoxycarbonylmethyloxy-1-pyrrolidino-propan-1-one

[0448] A solution of 8.0 g (20 mmol) of2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidino-propan-1-oneand 5 ml (48 mmol) of ethyl diazoacetate in 50 ml of methylene chlorideis mixed with 2.0 ml of boron trifluoride-diethylether complex (16 mmol)at room temperature and refluxed for 14 hours. After cooling, thereaction solution is stirred into ice water and the organic phase isseparated off. The aqueous phase is extracted three times with methylenechloride, the combined organic phases are washed with saline solution,dried over sodium sulphate and concentrated by evaporation. The residueis dissolved in ethyl acetate and purified on silica gel, extractinginitially with petroleum ether, then with petroleum ether/ethyl acetate(1:1). The uniform fractions are combined and concentrated byevaporation.

[0449] Yield: 2.5 g (26% of theory),

[0450] R_(f) value: 0.6 (silica gel; ethyl acetate)

[0451] C₂₆H₃₃N₃O₆ (483.57)

[0452] Mass spectrum: (M+H)⁺=484

[0453] h.2-(4-methylamino-3-amino-phenyl)-2-methyl-3-ethoxycarbonylmethyloxy-1-pyrrolidino-propan-1-one

[0454] Prepared analogously to Example 1 f from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-ethoxymethyloxy-1-pyrrolidin-1-yl-propan-1-oneand hydrogen/palladium on activated charcoal.

[0455] Yield: 81% of theory,

[0456] R_(f) value: 0.40 (silica gel; methylene chloride/ethanol=19:1)

[0457] i.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl-benzimidazole

[0458] Prepared analogously to Example 1g/h from2-(4-methylamino-3-amino-phenyl)-2-methyl-3-ethoxycarbonylmethyloxy-1-pyrrolidino-propan-1-one,4-cyano-phenylglycine/O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and subsequently treated with glacial acetic acid.

[0459] Yield: 77% of theory,

[0460] R_(f) value: 0.40 (silica gel; methylene chloride/ethanol=19:1)

[0461] C₂₈H₃₃N₅O₄ (503.61)

[0462] Mass spectrum: (M+H)⁺=504

[0463] (M+Na)⁺=526

[0464] k.2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate

[0465] Prepared analogously to Example 11 from2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand hydrochloric acid/ammonium carbonate in ethanol.

[0466] Yield: 64% of theory,

[0467] R_(f) value: 0.25 (silica gel; methylene chloride/ethanol=4:1+1%glacial acetic acid)

[0468] C₂₈H₃₆N₆O₄×CH₃COOH (520.63/580.69)

[0469] Mass spectrum: (M+H)⁺=521

EXAMPLE 6

[0470]2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride

[0471] a.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-one

[0472] A solution of 1.2 g (3.0 mmol) of2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidino-propan-1-onein 20 ml of tetrahydrofuran is combined at room temperature with 1.3 mlof (9.3 mmol) of triethylamine. Then 0.27 ml (3.5 mmol) ofmethanesulphonylchloride are added dropwise at 2-5° C. After 2 hours atroom temperature the precipitate formed is suction filtered and thefiltrate is concentrated by evaporation. The crude product is reactedfurther without purification.

[0473] Yield: 1.4 g (98% of theory).

[0474] b.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-cyano-1-pyrrolidine-propan-1-one

[0475] A solution of 8.2 g (17 mmol) of2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-onein 125 ml of dimethylformamide is mixed with 1.8 g (27 mmol) ofpotassium cyanide and heated to 100° C. for 2 hours. After cooling, thereaction solution is stirred into ice water and extracted 3× with ethylacetate. The combined organic phases are washed with saline solution anddried over sodium sulphate. The crude product is dissolved in methylenechloride and purified on silica gel, eluting initially with methylenechloride, then with methylene chloride/ethanol (50:1 and 25:1). Theuniform fractions are combined and concentrated by evaporation.

[0476] Yield: 5.0 g (72% of theory)

[0477] R_(f) value: 0.45 (silica gel; methylene chloride/ethanol=19:1)

[0478] C₂₃H₂₆N₄O₃ (406.49)

[0479] Mass spectrum: M+=406

[0480] (M+Na)⁺=429

[0481] c.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one

[0482] Prepared analogously to Example 4g from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-cyano-1-pyrrolidino-propan-1-oneand tributyl tin azide.

[0483] Yield: 37% of theory,

[0484] R_(f) value: 0.55 (silica gel; methylene chloride/ethanol=9:1)

[0485] C₂₃H₂₇N₇O₃ (449.52)

[0486] Mass spectrum: (M+Na)⁺=472

[0487] (M−H)⁻=448

[0488] d.2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one

[0489] Prepared analogously to Example 1f from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-oneand hydrogen/palladium on activated charcoal.

[0490] Yield: 48% of theory,

[0491] R_(f) value: 0.3 (silica gel; methylene chloride/ethanol=9:1)

[0492] C₁₆H₂₃N₇O (329.41)

[0493] Mass spectrum: (M+H)⁺=330

[0494] (M−H)⁻=328

[0495] e.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0496] Prepared analogously to Example 1g/h from2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one,4-cyano-phenylglycine/O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and subsequently treating with glacial acetic acid.

[0497] Yield: 17% of theory,

[0498] R_(f) value: 0.25 (silica gel; methylene chloride/ethanol=9:1)

[0499] C₂₅H₂₇N₉O (469.55)

[0500] Mass spectrum: (M−H)⁻=468

[0501] f.2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride

[0502] Prepared analogously to Example 11 from2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand hydrochloric acid/ammonium carbonate in ethanol.

[0503] Yield: 25% of theory,

[0504] R_(f) value: 0.35 (Reversed phase RP8; 5% salinesolution/methanol=1:1)

[0505] C₂₅H₃₀N₁₀O×HCl (486.58/523.05)

[0506] Mass spectrum: (M+H)⁺=487

EXAMPLE 7

[0507]2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-diacetate

[0508]

[0509] a.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-azido-1-pyrrolidino-propan-1-one

[0510] Prepared analogously to Example 6b from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-oneand sodium azide in dimethylformamide.

[0511] Yield: 100% of theory,

[0512] R_(f) value: 0.75 (silica gel; ethyl acetate/petroleum ether=1:1)

[0513] C₂₂H₂₆N₆O₃ (422.49)

[0514] Mass spectrum: M+=422

[0515] b.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-amino-1-pyrrolidino-propan-1-one

[0516] A solution of 24.75 g (59 mmol) of2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-azido-1-pyrrolidino-propan-1-oneand 15.7 g (60 mmol) of triphenylphosphine in 250 ml of tetrahydrofuranand 1.8 ml of water is stirred for 60 hours at room temperature. Afterevaporation of the solvent the residue is purified over silica gel,eluting first with methylene chloride, then with methylenechloride/ethanol (50:1, 9:1, 8:2 and 7:3). The uniform fractions arecombined and concentrated by evaporation.

[0517] Yield: 21.7 g (93% of theory),

[0518] R_(f) value: 0.25 (Reversed phase RP8; 5% salinesolution/methanol=2:3)

[0519] C₂₂H₂₈N₄O₃ (396.49)

[0520] Mass spectrum: (M+H)⁺=397

[0521] c.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-one

[0522] Prepared analogously to Example 1c from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-amino-1-pyrrolidino-propan-1-oneand di-tert.butyldicarbonate/N-ethyl-diisopropylamine in dioxane.

[0523] Yield: 98% of theory,

[0524] R_(f) value: 0.55 (silica gel; methylene chloride/ethanol=19:1)

[0525] C₂₇H₃₆N₅O₄ (496.61)

[0526] Mass spectrum: M⁺496

[0527] (M+Na)⁺=519

[0528] (M−H)⁻=495

[0529] d.2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-one

[0530] Prepared analogously to Example 1f from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-oneand hydrogen/palladium on activated charcoal.

[0531] Yield: 23% of theory,

[0532] R_(f) value: 0.4 (silica gel; methylene chloride/ethanol=19:1)

[0533] C₂₀H₃₂N₄O₃ (376.5)

[0534] Mass spectrum: (M+Na)⁺=399

[0535] (M−H)⁻=375

[0536] e.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(tert.butyloxycarbonylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0537] Prepared analogously to Example 1g/h from2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(tert.butyloxycarbonylamino)-1-pyrrolidino-propan-1-one,4-cyano-phenylglycine/carbonyldiimidazole and subsequent treatment withglacial acetic acid.

[0538] Yield: 58% of theory,

[0539] R_(f) value: 0.5 (aluminium oxide; methylenechloride/ethanol=19:1)

[0540] C₂₉H₃₆N₆O₃ (516.65)

[0541] Mass spectrum: M⁺=516

[0542] (M+Na)⁺=539

[0543] f.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-aminomethyl-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0544] Prepared analogously to Example 1i from2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(tert.butyloxycarbonylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand 6N hydrochloric acid in dioxane.

[0545] Yield: 82% of theory,

[0546] R_(f) value: 0.25 (silica gel; methylene chloride/ethanol=9:1)

[0547] g.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0548] Prepared analogously to Example 1k from2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-aminomethyl-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand ethyl bromoacetate/potassium carbonate in acetone.

[0549] Yield: 25% of theory,

[0550] R_(f) value: 0.6 (silica gel; methylene chloride/ethanol=9:1)

[0551] C₂₈H₃₄N₆O₃ (502.62)

[0552] Mass spectrum: (M+H)⁺=503

[0553] (M+Na)⁺=525

[0554] (M−H)⁻=501

[0555] h.2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-diacetate

[0556] Prepared analogously to Example 1l from2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand hydrochloric acid/ammonium carbonate in ethanol.

[0557] Yield: 66% of theory,

[0558] R_(f) value: 0.35 (silica gel; methylene chloride/ethanol=4:1+1%glacial acetic acid)

[0559] C₂₈H₃₇N₇O₃×2 CH₃COOH (519.65/639.76)

[0560] Mass spectrum: (M+H)⁺=520

[0561] The following compounds are obtained analogously to Example 7:

[0562] (1)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-(2-ethoxycarbonyl-ethyl)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0563] (2)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycarbonylmethylsulphonyl)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0564] (3)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycar-bonylmethylaminocarbonyl-N-methyl-aminomethyl)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-hydrochoride

[0565] Yield: 55% of theory,

[0566] R_(f) value: 0.4 (Reversed phase RP8; 5% salinesolution/methanol=1:1)

[0567] C₃₀H₃₈N₈O₄×HCl (574.36/610.81)

[0568] Mass spectrum: (M+H)⁺=575

[0569] (M−H)⁻=573

[0570] (M+Cl)⁻=609/611 (Cl)

EXAMPLE 8

[0571](R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochloride(mixture of diastereomers)

[0572] A solution of 500 mg (0.84 mmol) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochloride(mixture of diastereomers) in 4 ml of water is mixed with 2.7 ml of 1Nsodium hydroxide solution and stirred for 45 minutes at roomtemperature. The pH value of the solution is adjusted to 3.5 by addingIN hydrochloric acid. The solution is concentrated by evaporation withthe addition of toluene and the residue is mixed with a little methanol.After the undissolved inorganic material has been filtered off, thefiltrate is concentrated by evaporation and triturated with ether. Thesolid formed is filtered off and dried.

[0573] Yield: 480 mg (100% of theory),

[0574] R_(f) value: 0.5 (Reversed phase RP8; 5% salinesolution/methanol=1:1)

[0575] C₂₆H₃₃N₇O₃×2 HCl (491.6/564.51)

[0576] Mass spectrum: (M+H)⁺=492

[0577] (M+Na)⁺=514

[0578] The following compounds are obtained analogously to Example 8:

[0579] (1)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride

[0580] Yield: 70% of theory,

[0581] R_(f) value: 0.45 (Reversed phase RP8; 5% salinesolution/methanol=1:1)

[0582] C₂₆H₃₃N₇O₃×2 HCl (491.6/564.51)

[0583] Mass spectrum: (M+H)⁺=492

[0584] (2)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride

[0585] Yield: 100% of theory,

[0586] R_(f) value: 0.5 (Reversed phase RP8; 5% salinesolution/methanol=1:1)

[0587] C₂₅H₂₉N₇O₃×2 HCl (475.55/548.46)

[0588] Mass spectrum: (M+H)⁺=476

[0589] (M−H)⁻=474

[0590] (3)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0591] Yield: 67% of theory,

[0592] R_(f) value: 0.46 (silica gel; 5% methylenechloride/methanol/conc. ammonia=4:0.9:0.1)

[0593] C₃₂H₃₅N₇O₄ (581.67)

[0594] Mass spectrum: (M+H)⁺=582

[0595] (M−H)⁻=580

[0596] (M+Na)⁺=604

[0597] (4)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride

[0598] Yield: 45% of theory,

[0599] R_(f) value: 0.4 (Reversed phase RP8; 5% salinesolution/methanol=1:1)

[0600] C₂₆H₃₂N₆O₄×HCl (492.58/529.03)

[0601] Mass spectrum: (M+H)⁺=493

[0602] (M−H)⁻=491

[0603] (5)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-(2-carboxyethyl)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0604] (6)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxymethylsulphonyl-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

[0605] (7)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxymethyaminocarbonyl)-N-methyl-aminomethyl)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-hydrochloride

[0606] Yield: 15% of theory,

[0607] R_(f) value: 0.5 (Reversed phase RP8; 5% salinesolution/methanol=1:1) C₂₈H₃₄N₈O₄×HCl (546.62/583.09)

[0608] Mass spectrum: (M+H)⁺=547

[0609] (M−H)⁻=545

[0610] (M+C)⁻=581/583 (Cl)

EXAMPLE 9

[0611] Dry ampoule containing 75 mg of active substance per 10 mlComposition: Active substance 75.0 mg Mannitol 50.0 mg water forinjections ad 10.0 ml

[0612] Preparation:

[0613] Active substance and mannitol are dissolved in water. Afterpackaging the solution is freeze-dried. To produce the solution readyfor use, the product is dissolved in water for injections.

EXAMPLE 10

[0614] Dry ampoule containing 35 mg of active substance per 2 ml

[0615] Composition: Active substance 35.0 mg Mannitol 100.0 mg water forinjections ad 2.0 ml

[0616] Preparation:

[0617] Active substance and mannitol are dissolved in water. Afterpackaging, the solution is freeze-dried.

[0618] To produce the solution ready for use, the product is dissolvedin water for injections.

EXAMPLE 11

[0619] Tablet containing 50 mg of active substance

[0620] Composition: (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3)Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesiumstearate  2.0 mg 215.0 mg 

[0621] Preparation:

[0622] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side.

[0623] Diameter of the tablets: 9 mm.

EXAMPLE 12

[0624] Tablet containing 350 mg of active substance

[0625] Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg(3) Maize starch  80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5)Magnesium stearate  4.0 mg 600.0 mg

[0626] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side.

[0627] Diameter of the tablets: 12 mm.

EXAMPLE 13

[0628] Capsules containing 50 mg of active substance

[0629] Composition: (1) Active substance 50.0 mg (2) Dried maize starch58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate  2.0 mg160.0 mg 

[0630] Preparation:

[0631] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0632] This powder mixture is packed into size 3 hard gelatin capsulesin a capsule filling machine.

EXAMPLE 14

[0633] Capsules containing 350 mg of active substance

[0634] Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose  30.0 mg (4) Magnesium stearate  4.0 mg430.0 mg

[0635] Preparation:

[0636] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0637] This powder mixture is packed into size 0 hard gelatin capsulesin a capsule filling machine.

EXAMPLE 15

[0638] Suppositories containing 100 mg of active substance 1 suppositorycontains: Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitanmonostearate 840.0 mg 2,000.0 mg  

[0639] Method:

[0640] The polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40° C. the ground active substance ishomogeneously dispersed in the melt. It is cooled to 38° C. and pouredinto slightly chilled suppository moulds.

What is claimed is:
 1. A compound of the formula

wherein R_(a) denotes a straight-chained C₁₋₃-alkyl group wherein thehydrogen atoms may be wholly or partially replaced by fluorine atoms andwhich is substituted in the 1 position by a pyrrolidinocarbonyl or2,5-dihydropyrrolocarbonyl group optionally substituted by a C₁₋₃-alkylgroup and by an amino group which is monosubstituted by acarboxy-C₁₋₄-alkyl, cyano-C₁₋₄alkyl or tetrazolyl-C₁₋₄alkyl group, or bya C₁₋₃-alkyl group which is terminally substituted by anN-(carboxy-C₁₋₃-alkylaminocarbonyl)-amino group optionally substitutedby a C₁₋₃-alkyl group at one or both amino nitrogen atoms, by acarboxy-C₁₋₃alkoxy, N-(carboxy-C₁₋₃alkyl)-amino,N-(C₁₋₃alkyl)-N-(carboxy-C₁₋₃-alkyl)-amino,N-(carboxy-C₁₋₃alkylsulphonyl)-amino,N-(C₁₋₃-alkyl)-N-(carboxy-C₁₋₃-alkylsulphonyl)-amino ortetrazolyl-C₁₋₃-alkyl group, R_(b) denotes a C₁₋₃-alkyl group and R_(c)denotes an amidino group, a cyano group or a 1,2,4-oxadiazol-3-yl groupsubstituted in the 5 position by a C₁₃-alkyl or phenyl group, while thephenyl substituent may be substituted by a fluorine, chlorine or bromineatom or by a C₁₋₃-alkyl group, wherein any carboxy group mentionedherein before may optionally be replaced by a group which can beconverted in vivo into a carboxy group, selected from a hydroxmethylgroup, a carboxy group esterified with an alcohol wherein the alcoholicmoiety is a C₁₋₆-alkanol, a phenyl-C₁₋₃-alkanol, a C₃₋₉-cycloalkanol,whilst a C₅₋₈-cycloalkanol may additionally be substituted by one or twoC₁₋₃-alkyl groups, a C₅₋₈-cycloalkanol, wherein a methylene group in the3 or 4 position is replaced by an oxygen atom or by an imino groupoptionally substituted by a C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl,phenyl-C₁₋₃-alkoxycarbonyl or C₂₋₆-alkanoyl group and the cycloalkanolmoiety may additionally be substituted by one or two C₁₋₃-alkyl groups,a C₄₋₇-cycloalkenol, a C₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, aC₃₋₅-alkinol or phenyl-C₃₋₅-alkinol, with the proviso that no bond tothe oxygen atom starts from a carbon atom which carries a double ortriple bond, a C₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol having atotal of 8 to 10 carbon atoms which may additionally be substituted inthe bicycloalkyl moiety by one or two C₁₋₃-alkyl groups, a1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formulaR_(d)—CO—O—(R_(e)CR_(f))—OH, wherein R_(d) denotes a C₁₋₈-alkyl,C₅₋₇-cycloalkyl, phenyl or phenyl-C₁₋₃-alkyl group, R_(e) denotes ahydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or phenyl group and R_(f)denotes a hydrogen atom or a C₁₋₃-alkyl group, or wherein any carboxygroup mentioned herein before may optionally be replaced by a groupwhich is negatively charged under physiological conditions, selectedfrom the group consisting of a tetrazol-5-yl,phenylcarbonylaminocarbonyl, trifluoromethylcarbonyl-aminocarbonyl,C₆-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino,trifluoromethylsulphonylamino, C₁₋₆-alkylsulphonylaminocarbonyl,phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl andperfluoro-C₁₋₃alkylsulphonylaminocarbonyl group, and wherein any aminoor imino group mentioned herein before may optionally be substituted bya group which can be cleaved in vivo, selected from the group consistingof a hydroxy group, a benzoyl group optionally mono- or disubstituted byfluorine, chlorine, bromine or iodine atoms or by C₁₋₃-alkyl orC₁₋₃-alkoxy groups, whilst the substituents may be identical ordifferent, a pyridinoyl group, a C₁₋₁₆-alkanoyl group, a3,3,3-trichloropropionyl or allyloxycarbonyl group, aC₁₋₁₆-alkoxycarbonyl or C₁₋₁₆-alkylcarbonyloxy group wherein hydrogenatoms may be wholly or partially replaced by fluorine or chlorine atoms,a phenyl-C₁₋₆-alkoxycarbonyl group, a 3-amino-propionyl group whereinthe amino group may be mono- or disubstituted by C₁₋₆-alkyl orC₃₋₇-cycloalkyl groups and the substituents may be identical ordifferent, a C₁₋₃alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl,R_(d)—CO—O—(R_(d)CR_(f))—O—CO, C₁₋₆-alkyl-CO—NH—(R_(g)CR_(h))—O—CO orC₁₋₆-alkyl-CO—O—(R_(g)CR_(h))—(R_(g)CR_(h))—O—CO group wherein R_(d) toR_(f) are as hereinbefore defined, R_(g) and R_(h), which may beidentical or different, denote hydrogen atoms or C₁₋₃-alkyl groups andwherein the saturated alkyl and alkoxy moieties which contain more than2 carbon atoms mentioned in the above definitions also include thebranched isomers thereof such as the isopropyl, tert.butyl, isobutylgroup, or a tautomer or a salt thereof.
 2. A compound of the formula Iaccording to claim 1, wherein R_(a) denotes an ethyl group which issubstituted in the I position by a 2,5-dihydropyrrolocarbonyl groupoptionally substituted by a methyl group and by an amino group which issubstituted by a C₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl group, by acarboxy-C₁₋₄alkyl, cyclohexyloxycarbonyl-C₁₋₄-alkyl ortetrazolyl-C₁₋₄-alkyl group, or by a C₁₋₃-alkyl group which isterminally substituted by an N-(carboxy-C₁₋₃alkylaminocarbonyl)-amino orN-(C₁₋₃alkoxycarbonyl-C₁₋₃-alkylaminocarbonyl)-amino group optionallysubstituted at one or both amino nitrogen atoms by a C₁₋₃-alkyl group,by a carboxy-C₁₋₃-alkoxy, C₁₃-alkoxycarbonyl-C₁₋₃alkoxy,N-(C₁₋₃-alkyl)-N-(carboxy-C₁₋₃-alkyl)-amino,N-(C₁₋₃-alkyl)-N-(C₁₋₃alkoxycarbonyl-C₁₋₃alkyl)-amino,N-(C₁₋₃alkyl)-N-(carboxy-C₁₋₃alkylsulphonyl)-amino orN-(C₁₋₃-alkyl)-N-(C₁₋₃-alkoxycarbonyl-C₁₋₃alkylsulphonyl)-amino ortetrazolyl-C₁₋₃alkyl group, R_(b) denotes a methyl group and R_(c)denotes an amidino group optionally substituted by a benzoyl,methylbenzoyl or fluorobenzoyl group or R_(a) denotes an ethyl groupwhich is substituted in the 1 position by a pyrrolidinocarbonyl groupand by an amino group, whilst the amino group is substituted by anethoxycarbonylmethyl group, by a carboxymethyl, propyloxycarbonylmethyl,isopropyloxycarbonylmethyl, isobutyloxycarbonylmethyl,cyclohexyloxycarbonylmethyl, 3-(C₂₋₃-alkoxycarbonyl)-propyl ortetrazolylmethyl group, R_(b) denotes a methyl group and R_(c) denotesan amidino group substituted by a benzoyl, methylbenzoylor fluorobenzoylgroup or R_(a) denotes an ethyl group which is substituted in the 1position by a pyrrolidinocarbonyl group substituted in the 2 position bya methyl group and by an amino group, whilst the amino group issubstituted by a carboxymethyl or ethoxycarbonylmethyl group, R_(b)denotes a methyl group and R_(c) denotes an amidino group or R_(a)denotes an ethyl group which is substituted in the 1 position by apyrrolidinocarbonyl group and by an amino group substituted by acarboxymethyl or C₃₋₄-alkoxycarbonylmethyl group or by a methyl group,whilst the methyl group is substituted by a carboxymethoxy,ethoxycarbonylmethoxy, ethoxycarbonylmethylamino,N-(2-carboxyethyl)-N-methyl-amino,N-[2-(C₁₋₃-alkoxycarbonyl)-ethyl]-N-methyl-amino,N-(carboxymethylaminocarbonyl)-N-methyl-amino,N-(C₁₋₃-alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino,N-(carboxymethylsulphonyl)-N-methyl-amino orN-(C₁₋₃alkoxycarbonylmethylsulphonyl)-N-methyl-amino group, R_(b)denotes a methyl group and R_(c) denotes an amidino group, or a tautomeror salt thereof.
 3. A compound selected from the group consisting of:(a)(R)-2-[4-[N-(4-trifluoromethyl-phenylcarbonyl)amidino]-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,(b)(R)-2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,(c)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-methoxy-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,(d)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-dimethylamino-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,(e)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-(2-methylphenyl)-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand (f)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,or a tautomer or physiologically acceptable salt thereof.
 4. Aphysiologically acceptable salt of a compound according to claim 1 or 2,wherein R_(c) denotes an amidino group.
 5. A pharmaceutical compositioncontaining a compound according to claim 1 or 2, wherein R_(c) denotesan amidino group, or a physiologically acceptable salt thereof, or acompound according to claim 3, and a pharmaceutically acceptablecarrier.
 6. A method for inhibiting the formation of thromboses or fortreating thromboses which method comprises administering to a host inneed of such treatment an antithrombotic amount of a compound accordingto claim 1 or 2, wherein R_(c) denotes an amidino group, or aphysiologically acceptable salt thereof, or a compound according toclaim 3.